Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.8.1.12 (trypanothione reductase)
355 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antioxidant defence plays a crucial role in rapidly growing and multiplying organisms, including parasites and tumor cells. Apart from reactive oxygen species (ROS) produced in endogenous reactions, parasites are usually exposed to high ROS concentrations imposed by the host immune system. The glutathione and thioredoxin systems represent the two major antioxidant defence lines in most eukaryotes and prokaryotes. Trypanosomatids, however, are characterized by their unique trypanothione system. These systems are NADPH-dependent and based on the catalytic activity of the flavoenzymes glutathione reductase, trypanothione reductase and thioredoxin reductase (TrxR), respectively. TrxR reduces the 12-kDa protein thioredoxin (Trx), which in turn provides elcctrons to ribonucleotide reductase, thioredoxin peroxidases (TPxs), certain transcription factors and other target molecules. Comparing the thioredoxin systems of different parasites and their respective host cells enhances our understanding of parasite biology and evolution, of parasite-host interactions and mechanisms of drug resistance. It furthermore opens avenues for the development of novel antiparasitic compounds. Here we review the current knowledge on the Trx systems of eukaryotic parasites, finally focusing on the malarial parasite Plasmodium falciparum.
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PMID:The thioredoxin system of Plasmodium falciparum and other parasites. 1216 15

Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease and the three forms of leihmaniasis. New drugs against these parasitic protozoa are urgently needed since the currently available chemotherapy is not at all satisfying. One promising approach towards the development of new drugs is based on the design of specific enzyme inhibitors. Trypanosomes and leishmania possess a unique thiol metabolism in which the ubiquitous glutathione/glutathione reductase system is replaced by trypanothione and trypanothione reductase. The dithiol trypanothione is the key molecule for the synthesis of DNA precursors, the homeostasis of ascorbate, the detoxification of hydroperoxides, and the sequestration/export of thiol conjugates. Synthesis and reduction of trypanothione are essential for the maintenance of a reducing intracellular milieu which renders the respective enzymes attractive drug target molecules. Here we present the current state of knowledge of the thiol metabolism of trypanosomatids, comprising the trypanothione/tryparedoxin, thioredoxin, and ovothiol systems of the parasites. The most effective inhibitors of the enzymes known to date, their mode of action, and the (dis)advantages of different types of inhibitors as potential drug candidates will be discussed.
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PMID:Enzymes of the trypanothione metabolism as targets for antitrypanosomal drug development. 1217 83

9-Aminoacridines and (terpyridine)platinum(II) complexes are competitive and irreversible inhibitors, respectively, of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease. Four chimeric compounds in which 2-methoxy-6-chloro-9-aminoacridine was covalently linked to the (2-hydroxyethanethiolate)(2,2':6',2' '-terpyridine)platinum(II) complex were synthesized and studied as inhibitors of the parasite enzyme. The derivatives differed by the nature and/or the length of the spacer connecting the two aromatic systems. All four compounds were effective mixed type inhibitors of trypanothione reductase with K(i) and K(i)' values of 0.3-4 and 2-11 microM, respectively. The most potent inhibitor had an ethylthioether linkage between the two aromatic ring systems, and the other compounds contained an alkyl ether group with 4-6 methylene groups. In contrast to the parasite enzyme, human glutathione reductase, the closest related host enzyme was not inhibited by these compounds. The finding that the conjugation of a competitive and an irreversible inhibitor can give rise to reversible mixed type inhibitors underlines the difficulties associated with inhibitor design based on the three-dimensional structure of trypanothione reductase.
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PMID:Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase. 1223 31

The NADPH:2-ketopropyl-coenzyme M oxidoreductase/carboxylase (2-KPCC) is the terminal enzyme in a metabolic pathway that results in the conversion of propylene to the central metabolite acetoacetate in Xanthobacter autotrophicus Py2. This enzyme is an FAD-containing enzyme that is a member of the NADPH:disulfide oxidoreductase (DSOR) family of enzymes that include glutathione reductase, dihydrolipoamide dehydrogenase, trypanothione reductase, thioredoxin reductase, and mercuric reductase. In contrast to the prototypical reactions catalyzed by members of the DSOR family, the NADPH:2-ketopropyl-coenzyme M oxidoreductase/carboxylase catalyzes the reductive cleavage of the thioether linkage of 2-ketopropyl-coenzyme M, and the subsequent carboxylation of the ketopropyl cleavage product, yielding the products acetoacetate and free coenzyme M. The structure of 2-KPCC reveals a unique active site in comparison to those of other members of the DSOR family of enzymes and demonstrates how the enzyme architecture has been adapted for the more sophisticated biochemical reaction. In addition, comparison of the structures in the native state and in the presence of bound substrate indicates the binding of the substrate 2-ketopropyl-coenzyme M induces a conformational change resulting in the collapse of the substrate access channel. The encapsulation of the substrate in this manner is reminiscent of the conformational changes observed in the well-characterized CO2-fixing enzyme ribulose 1,5-bisphosphate carboxylase/oxidase (Rubisco).
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PMID:Structural basis for CO2 fixation by a novel member of the disulfide oxidoreductase family of enzymes, 2-ketopropyl-coenzyme M oxidoreductase/carboxylase. 1239 15

Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease, and the different manifestations of leishmaniasis. New drugs against these parasitic protozoa are urgently needed since the current drugs are unsatisfactory, in particular due to serious adverse side effects. In trypanosomes and leishmanias, the nearly ubiquitous glutathione/glutathione reductase system is replaced by trypanothione and trypanothione reductase. The essential role of trypanothione reductase in the parasite thiol metabolism and its absence from the mammalian host render the enzyme a highly attractive target molecule for a structure-based drug development against trypanosomatids. This article provides an overview on the known classes of trypanothione reductase inhibitors and their in vitro activity against parasitic protozoa. The (dis)advantages of the different types of compounds as potential drug candidates as well as modern computer-based approaches to the identification of new leads are discussed.
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PMID:Parasite-specific trypanothione reductase as a drug target molecule. 1270 93

The bis(glutathionyl)spermidine trypanothione exclusively occurs in parasitic protozoa of the order Kinetoplastida, such as trypanosomes and leishmania, some of which are the causative agents of several tropical diseases. The dithiol is kept reduced by the flavoenzyme trypanothione reductase and the trypanothione system replaces in these parasites the nearly ubiquitous glutathione/glutathione reductase couple. Trypanothione is a reductant of thioredoxin and tryparedoxin, small dithiol proteins, which in turn deliver reducing equivalents for the synthesis of deoxyribonucleotides as well as for the detoxification of hydroperoxides by different peroxidases. Depending on the individual organism and the developmental state, the parasites also contain significant amounts of glutathione, mono-glutathionylspermidine and ovothiol, whereby all four low molecular mass thiols are directly (trypanothione and mono-glutathionylspermidine) or indirectly (glutathione and ovothiol) maintained in the reduced state by trypanothione reductase. Thus the trypanothione system is central for any thiol regeneration and trypanothione reductase has been shown to be an essential enzyme in these parasites. The absence of this pathway from the mammalian host and the sensitivity of trypanosomatids toward oxidative stress render the enzymes of the trypanothione metabolism attractive target molecules for the rational development of new drugs against African sleeping sickness, Chagas' disease and the different forms of leishmaniasis.
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PMID:The parasite-specific trypanothione metabolism of trypanosoma and leishmania. 1275 84

The enzyme trypanothione reductase is a recognised drug target in trypanosomatids and has been used in the search of new compounds with potential activity against diseases such as leishmaniasis, Chagas disease and African trypanosomiasis. 8-Methoxy-naphtho [2,3-b] thiophen-4,9-quinone was selected in a screening of natural and synthetic compounds using an in vitro assay with the recombinant enzyme from Trypanosoma cruzi. Its mode of inhibition fits a non-competitive model with respect to the substrate (trypanothione) and to the co-factor (NADPH), with Ki-values of 5 and 3.6 M, respectively. When tested against human glutathione reductase, this compound did not display any significant inhibition at 100 M, indicating a good selectivity against the parasite enzyme.
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PMID:8-Methoxy-naphtho[2,3-b]thiophen-4,9-quinone, a non-competitive inhibitor of trypanothione reductase. 1293 75

Mammalian thioredoxin reductases (TrxR) are important selenium-dependent antioxidant enzymes. Quinones, a wide group of natural substances, human drugs, and environmental pollutants may act either as TrxR substrates or inhibitors. Here we systematically analyzed the interactions of TrxR with different classes of quinone compounds. We found that TrxR catalyzed mixed single- and two-electron reduction of quinones, involving both the selenium-containing motif and a second redox center, presumably FAD. Compared with other related pyridine nucleotide-disulfide oxidoreductases such as glutathione reductase or trypanothione reductase, the k(ca)(t)/K(m) value for quinone reduction by TrxR was about 1 order of magnitude higher, and it was not directly related to the one-electron reduction potential of the quinones. A number of quinones were reduced about as efficiently as the natural substrate thioredoxin. We show that TrxR mainly cycles between the four-electron reduced (EH(4)) and two-electron reduced (EH(2)) states in quinone reduction. The redox potential of the EH(2)/EH(4) couple of TrxR calculated according to the Haldane relationship with NADPH/NADP(+) was -0.294 V at pH 7.0. Antitumor aziridinylbenzoquinones and daunorubicin were poor substrates and almost inactive as reversible TrxR inhibitors. However, phenanthrene quinone was a potent inhibitor (approximate K(i) = 6.3 +/- 1 microm). As with other flavoenzymes, quinones could confer superoxide-producing NADPH oxidase activity to mammalian TrxR. A unique feature of this enzyme was, however, the fact that upon selenocysteine-targeted covalent modification, which inactivates its normal activity, reduction of some quinones was not affected, whereas that of others was severely impaired. We conclude that interactions with TrxR may play a considerable role in the complex mechanisms underlying the diverse biological effects of quinones.
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PMID:Interactions of quinones with thioredoxin reductase: a challenge to the antioxidant role of the mammalian selenoprotein. 1460 85

Trypanothione reductase is a key enzyme in the trypanothione-based redox metabolism of pathogenic trypanosomes. Because this system is absent in humans, being replaced with glutathione and glutathione reductase, it offers a target for selective inhibition. The rational design of potent inhibitors requires accurate structures of enzyme-inhibitor complexes, but this is lacking for trypanothione reductase. We therefore used quinacrine mustard, an alkylating derivative of the competitive inhibitor quinacrine, to probe the active site of this dimeric flavoprotein. Quinacrine mustard irreversibly inactivates Trypanosoma cruzi trypanothione reductase, but not human glutathione reductase, in a time-dependent manner with a stoichiometry of two inhibitors bound per monomer. The rate of inactivation is dependent upon the oxidation state of trypanothione reductase, with the NADPH-reduced form being inactivated significantly faster than the oxidized form. Inactivation is slowed by clomipramine and a melarsen oxide-trypanothione adduct (both are competitive inhibitors) but accelerated by quinacrine. The structure of the trypanothione reductase-quinacrine mustard adduct was determined to 2.7 A, revealing two molecules of inhibitor bound in the trypanothione-binding site. The acridine moieties interact with each other through pi-stacking effects, and one acridine interacts in a similar fashion with a tryptophan residue. These interactions provide a molecular explanation for the differing effects of clomipramine and quinacrine on inactivation by quinacrine mustard. Synergism with quinacrine occurs as a result of these planar acridines being able to stack together in the active site cleft, thereby gaining an increased number of binding interactions, whereas antagonism occurs with nonplanar molecules, such as clomipramine, where stacking is not possible.
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PMID:Two interacting binding sites for quinacrine derivatives in the active site of trypanothione reductase: a template for drug design. 1510 53

The activity of trypanothione reductase in Leishmania amazonensis was evaluated and it was demonstrated that TR is expressed in the soluble fractions of infective promastigotes and amastigotes, while non-infective promastigotes expressed the enzyme at basal levels. This data allows an association of enzyme activity and the infective capacity of the parasite. We have also previously demonstrated that amidine compounds (N, N'-diphenyl-4-methoxy-benzamidine and pentamidine) were active against this parasite. Here, experiments concerning the effect of these compounds on TR activity, showed that both compounds significantly inhibited the enzyme. However, against glutathione reductase, only pentamidine showed a significant inhibitory action, suggesting an association with the toxic effects of this drug used in the clinic for the treatment of leishmaniasis.
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PMID:Trypanothione reductase activity is prominent in metacyclic promastigotes and axenic amastigotes of Leishmania amazonesis. Evaluation of its potential as a therapeutic target. 1520 94


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